t I Hepatic Resection for Metastatic Colorectal Adenocarcinoma: A Proposal of a Prognostic Scoring System I ~:

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1 Hepatic Resection for Metastatic Colorectal Adenocarcinoma: A Proposal of a Prognostic Scoring System Shunzaburo Iwatsuki MD PhD FACS Igor Dvorchik phd Juan R Madariaga MD FACS J Wallis Marsh MD FACS Forrest Dodson MD Andrew C Bonham MD David A Geller MD Timothy J Gayowski MD FACS John J Fung MD PhD FACS Thomas E Stan! MD phd FACS Background: Hepatic resection for metastatic colorectal cancer provides excellent longterm results in a substantial proportion of patients. Although various prognostic risk factors have been identified there has been no dependable staging or prognostic scoring system for metastatic hepatic tumors. Study Design: Various clinical and pathologic risk factors were examined in 35 consecutive patients who underwent primary hepatic resections for metastatic colorectal cancer. Survival rates were estimated by the Cox proportional hazards model using the equation: Set) = [So(t)]exp(R- R..) where So(t) is the survival rate of patients with none of the identified risk factors and Ro=O. Results: Preliminary multivariate analysis revealed that independently significant negative prognosticators were: (1) positive surgical margins (2) extrahepatic tumor involvement including the lymph node(s) (3) tumor number of three or more (4) bilobar tumors and (5) time from treatment of the primary tumor to hepatic recurrence of 3 months or less. Because the survival rates of the 62 patients with positive margins or extrahepatic tumor were uniformly very poor multivariate analysis was repeated in the remaining 243 patients who did not have these lethal risk factors. The reanalysis revealed that independently significant poor prognosticators were: (1) tumor number of three or more (2) tumor size greater than 8cm (3) time to hepatic recur-. rence of3 months or less and (4) bilobar tumors. Risk scores (R) for tumor recurrence of the culled cohort (n = 243) were calculated by summation of coefficients I No competing interests d R=ived January ; Revised March ; Accepted April From the Department of Surgery. the Thomas E Starz1 Transplantation Institutc. University of Pittsburgh Medical Center. Pittsburgh. P A. Correspondcnce address: Shunzaburo Iwatsuki. MD. PhD. FACS. Department of Surgery. Thomas E Starz1 Transplantation Institute. 4th Floor Falk Clinic. 361 Fifth Ave. Pittsburgh. PA from the multivariate analysis and were divided into five groups: grade 1 no risk factors (R = ); grade 2 one risk factor (R=.3 to.7); grade 3 two risk factors (R=.7 to 1.1); grade 4 three risk factors (R= 1.2 to 1.6); and grade 5 four risk factors (R 1.6). Grade 6 consisted of the 62 culled patients with positive margins or extrahepatic tumor. Kaplan-Meier and Cox proportional hazards estimated 5-year survival rates of grade 1 to 6 patients were 48.3% and 48.3% 36.6% and 33.7% 19.9% and 17.9%11.9% and 6.4% % and 1.1 % and % and % respectively (p <.1). Conclusions: The proposed risk-score grading predicted the survival differences extremely well. Estimated survival as determined by the Cox proportional hazards model was similar to that determined by the Kaplan Meier method. Verification and further improvements of the proposed system are awaited by other centers or international collaborative studies. (J Am CoIl Surg 1999;189: by the American College of Surgeons) Hepatic resection for metastases from colorectal carcinoma can be performed quite safely and provides excellent longterm results in a substantial proportion of patients Now that various clinical and pathologic risk factors have been identifiedi-18 the efforts of investigation should be shifted to establishing an accurate staging system for metastatic hepatic tumors or a dependable prognostic scoring method to predict the results after curative operations. We examined our 35 consecutive patients with colorectal metastases who underwent hepatic resection with curative intent to identify clinical and pathologic prognosticators. We propose here a new prognostic scoring methoq and associated proportional hazards model for survival. I. : t I '. '; i.. ' I : 1999 by the American College of Surgeons Published by Elsevier Science Inc 291 ISSN /991$21- PH SI (99)89-7

2 lwatsuki et a1 Hepatic Resection Prognostic Scoring System J Am Coli Surg METHODS Patients and tumors During the IS-year period between 1981 and consecutive patients were treated with primary hepatic resection for hepatic metastases from adenocarcinoma of colorectal origin at the University of Pittsburgh Medical Center. All hepatic resections were carried out with curative intent. There were 178 men and 127 women. Their ages ranged from 26 to 82 years (mean ± SE 6 ±.6 years). The primary tumor was located in the right colon of 71 patients (23.3%) the left colon of 156 (51.1 %) and the rectum of 78 (25.6%). Five patients (1.6%) had Dukes A (stage I) primary tumors and 7 (23.%) had Dukes B (stage II). Dukes C (stage III) tumors represented the largest group with 141 patients (46.2%); 89 patients (29.2%) had synchronous hepatic metastases (Dukes D; stage IV) Most patients with Dukes D tumors underwent hepatic resection within the first 3 months after their colorectal resection. Twenty-three patients were not referred or evaluated until after this interval. Metastases to the mesenteric lymph nodes were present at the time of colorectal operation in 154 patients (5.5%) and were absent in 148 (48.5%). The status of lymph node involvement was not available in three patients. The interval between the primary colorectal resection and hepatic resection ranged from - 6 months (primary not discovered until after resection) to 228 months with a median of 16 months. One hundred thirty-seven patients (44.9%) had solitary lesions 75 (24.6%) had 2 lesions 31 (1.2%) had 3 lesions and 62 (21.%) had 4 or more lesions (as many as 11). The size of the hepatic metastasis ranged from 1.2 to 18 cm with a median of 5 cm; the size exceeded 8 cm in 48 (15.7%) of the 35 patients. The hepatic metastases were unilobar in 2 patients (65.6%) and bilobar in the other 15 (34.4%). At the time of hepatic resection abdominal lymph node metastases were present in 9 patients (3.%) and absent in 296 (97.%). Because of direct tumor invasion the diaphragm the right adrenal gland the greater omentum or localized peritoneal seeding were removed in continuity with the resected liver in 32 patients (1.5%). The metastatic tumors were histologically well differentiated (grade 1) in 59 patients (19.3%) moderately differentiated (grade 2) in 239 (78.4%) and poorly differentiated (grade 3) in 7 (2.3%) Right or left hepatic lobectomy was performed in 158 patients more than lobectomy (trisegmentectomy extended lobectomy and lobectomy plus wedge resection) in 85 patients multiple bilateral wedge resections in 2 patients and less than lobectomy (left lateral segmentectomy and nonanatomic resection) in 42 patients. Of note 243 (79.7%) of the 35 patients were treated by lobectomy or greater hepatic resection. Despite the curative intent of resection 28 (9.2%) of the 35 patients had microscopically positive margins at postoperative pathologic examinations although all gross tumors were removed. After hepatic resection with curative intent 22 (66.2%) of the 35 patients received adjuvant chemotherapy. Although no single chemotherapeutic protocol was applied the usual regimen contained 5-FU with levamisole or leucovorin for 6 months. Recurrent tumors after hepatic resection were surgically removed in 32 patients including 12 thoracoscopic pulmonary resections 11 hepatic reresections 3 bone resections (2 sacrum 1 sternum) 3 abdominal-wall resections 1 adrenalectomy and 2 colectomies. Data analysis We retrospectively reviewed all available inpatient and outpatient records including operative and pathologic reports. Patient followup was performed prospectively every 6 months after hepatic resection and the results were summarized as of June The median followup period was 32 months. The 16 clinical and pathologic risk factors listed in Table 1 were examined for prognostic influence. Patient survival time was calculated from the date of hepatic resection until death and tumor-free survival was determined from the date of resection until the time of tumor recurrence. Survival curves were generated with the method of Kaplan and Meier and were compared using the log-rank test. A multivariate stepwise Cox regression analysis (backward elimination method) was performed to identify the factors that were independently associated with mortality and tumor recurrence. A two-sided p value of <.5 was considered statistically significant.

3 Vol No.3. September 1999 Iwatsuki et a1 Hepatic Resection Prognostic Scoring System 293 Table 1. Influences of Various Clinical and Pathologic Risk Factors on Overall Patient and Tumor-Free Survival Overall patient survival Tumor-free survival P p Characteristic n 3 y (%) 5 y (%) 1 y (%) Value 3 y (%) 5 y (%) 1 y (%) Value Patient Gender Male NS <.3 Female Age (y) = S NS NS S Primary tumor Site Rectum 78 SO.l NS NS Left colon S Right colon Dukes classification A+B 7S NS <.6 C D (synchronous) Dukes classification A+B < <.2 C+D Lymph node Negative < <.2 Positive Hepatic metastases Interval (mo) = NS NS H Interval (mo) = < < No. of tumors < < ;;:: No. of tumors < <.1 ;;:: Size (em) = NS NS S Size (em) = < < Distribution Unilobar < <.1 Bilobar ! :1 (Table 1 continues on ncxt page) " I: I'. '.

4 -'----"-" Iwatsuki et al Hepatic Resection Prognostic Scoring System J Am Colt Surg 1 -fi Table 1. Continued rrulpatientsunnv.u Characteristic n 3 y(%) 5 y(%) 1 y (%) Node metastasis No Yes Metastasis No Yes Differentiation Grade Grade Grade Surgery Margin lcm :51cm Involved Resection Multiple wedges More chan lobe Lobectomy Less than lobe Adjuvant therapy No Yes Surgery for recurrence No Yes Tumor-free sunrival p p Value 3 y(%) 5 y(%) 1 y(%) Value < < < '<.1 NS NS < < < < NS NS < < :'- ; "- j )" ;;. RESULTS Early mortality and morbidity Ther were no. deaths within the first 3 days after hpalc resectlon although three patients died WIthIn 9 days (perioperative mortality of less than 1 o). One death was in a 71-year-old man after right trlsegmentectomy who developed liver failure and stress-ulcer bleeding. Two other deaths from liver failure and septicemia after extended right lobectomy were in 62- and 67-year-old men... In dditon there were 16 cases of severe hyperbilirubmemia (serum total bilirubin greater than 8 mg/l ml) 7 subphrenic abscesses 5 cases of prolonged ascites or pleural effusion 2 deep vein thromboses 2 prolonged bile leaks 2 cardiac arrhythmias and 1 stress ulcer with bleeding. These complications occurred in 25 (8.2%) of the 35 patients (one patient had multiple complications) and were resolved without permanent consequences. Survival As of}une (64.9%) of the 35 patients were known to be dead with tumor recurrence 12 (3.9%) were dead without tumor recurrence 67 (22.%) were alive and free of tumor recurrence and 28 (9.2%) were alive with tumor recurrence. None of the patients were lost to followup. Ten-year overall and tumor-free Kaplan-Meier survival curves for the 35 patients after hepatic resection are depicted in Figure 1; 5-year overall survival was 32.3%. The tumor-free survival at this milestone was 23.%. Examinations of clinical and pathologic risk factors The influences of 16 clinical and pathologic risk factors on overall patient and tumor-free survival rates w.ere examined (Table 1). For both end points a significantly better prognosis was associated with the following: (1) primary colorectal cancer of Dukes A and B (2) no metastasis to the mesenteric lymph nodes at the time of colorectal operation (3) interval between colorectal operation and hepatic resection of longer than 3 months (4) cwo or fewer hepatic metastases (5) greatest tumor diameter of Scm or less (6) unilobar distribution of hepatic metastases (7) no nodal metastasis at the time of hepatic resection (8) no distant metastasis at the time of hepatic

5 p I Vol. 189 No.3 September 1999 lwatsuki et al Hepatic Resection Prognostic Scoring System 295 resection (9) microscopically negative surgical margins and (1) lobectomy or smaller hepatic resectlon. The patients whose recurrent hepatic metastases could be resected surgically lived longer than those whose recurrent tumors were not resected. Although overall patient survival was similar for men and women tumor-free survival for men was significantly better than that for women (Table 1). Multivariate analysis Multivariate analysis based on the 35 patients identified the following significant poor prognosticators for overall and tumor-free survival: (1) positive surgical margins (2) extrahepatic metastasis including lymph nodes (3) tumor number of three or more (4) bilobar distribution of hepatic metastases and (5) interval between colorectal resection and hepatic resection of 3 months or less. Because the survival of the 62 patients who had positive surgical margins and extrahepatic metastasis (including lymph nodes) was uniformly poor univariate and multivariate analyses were repeated after excluding these 62 patients to identify the independent factors that could be used to calculate a risk score. The repeat univariate analysis on the remaining 243 patients confirmed the significant effect of all previously discovered risk factors except for the status of the mesenteric lymph nodes at the time of colorectal operation (p.17). The lymph node status at the time of colorectal operation was better represented by Dukes classification (positive mesenteric lymph nodes are limited to Dukes C and D). The remaining six risk factors (size number lobar distriburion time to recurrence Dukes classification and extent of resection) met the assumption of proportionality of hazards by assessment of logminus-log survival plot. A stepwise Cox regression analysis with backward selection was used to determine independent predictors of mortality and tumor recurrence. The :::.t :l en.. 5 CD 4 III "3 E 3 :l 2 1 "'... (79).... Tumor-Free Survival Overall Patient Survival (21) "'--"" (48) (18) Time After Liver Resection (years) Figure 1. Ten-year overall patient and rumor-free Kaplan-Meier survival. likelihood ratio test based on maximum partial likelihood estimates was used for elimination of confounding variables from the model. Variables were considered eligible for removal if the likelihood ratio test significance level was ::::::.1. Four variables (tumor number greater than two tumor size greater than 8 em interval of 3 months or less and bilobar metastases) were found ro be independent predictors of tumor recurrence (Table 2). The results of the multivariate analysis for overall patient survival are shown in Table 3. The exclusion of Dukes classification can be explained by the strong inverse relation (p <. 1) between the time to recurrence (interval) and Dukes stages (the shorter the interval the more advanced the Dukes stage). The extent of hepatic resection is an immediate consequence of the size number and distriburion of metastases which explains its exclusion from a set of independent predictors. Table 2. Significant Prognostic Risk Factors for Tumor Recurrence (Tumor-Free Survival) Identified by Multivariate Analysis* Risk factor Tumor number 2 Tumor size Bcm Interval ::::; 3 mo Bilobar rumors Coefficient (B) E.xcludes [he (2 pltients with positive surgical mlrgins. lymph node invasion. or disllnt metastas.s. Relative risk % Confidence interval

6 296 lwatsuki et al Hepatic Resection Prognostic Scoring System J Am Coil Surg Table 3. Significant Prognostic Risk Factors for Mortality (Overall Patient Survival) Determined by Multivariate Analysis* 95% Confidence Risk factor Coefficient (B) Relative risk interval Tumor number Tumor size 8cm Interval 3 mo Bilobar tumors 'Excludes the 62 patients with positive surgical margins lymph node invasion or distant metastasis. Calculation of risk score and prediction of survival Based on the results of the multivariate analysis the risk score can be calculated for each patient by the following formula: Risk score (R) = BIXI + B 2 X 2 + B3X3 + B 4 X 4 where B = coefficient from the Cox model (Tables 2 3) and = when the risk factor is absent or = 1 when the risk factor is present. Correspondingly the probability of which patient with risk score R will be recurrence-free t years after hepatic resection (S(t)) can be calculated by the following;l: S(t) = [So(t)]exp(R-R) where R is the. nsk score corresponding to the baseline survival function So(t). Because all of the four risk factors are presented as binary variables So(t) was calculated for a patient with no risk factors. The cumulative tumorfree survival (Kaplan-Meier) of the 243 patients was then compared with the predicted probability of cohort tumor-free survival after hepatic resection (S(t»). The fit of the developed model was assessed heuristically by comparison of overall patient and tumorfree survival rates estimated by the Kaplan-Meier method versus the predicted survival by the Cox model of probability for various patient risk groups. As shown in Table 4 Set) agrees reasonably well with tumor-free survival as determined by the Kaplan Meier method. Practical application of risk score Risk scores for tumor-free survival were grouped into the following strata: grade 1 none of the four risk factors present (risk score = ); grade 2 one of the four risk factors present (risk score =.338 to.6286); grade 3 two of the four risk factors present (risk score =.722 to l.1 1); grade 4 three of the four risk factors present (risk score = to 1.494); grade 5 all of the four risk factors present (risk score = ); and grade 6 positive surgical margins and lymph node or distant metastasis. Tumor-free survival rates (Kaplan-Meier) for the above-defined six grades of patients are depicted in Figure 2 and the tumor-free survival rates calculated by Set) (Cox model) are shown in Figure 3 for comparison. Note that the survival curves were similar. Overall patient survival rates (Kaplan-Meier) of the six grades of patients and those calculated by Set) are shown in Figures 4 and 5 respectively. DISCUSSION Hepatic resection for metastatic colorectal cancer can now be performed with minimal surgical risks. With this treatment an overalls-year survival rate of25% to 4% has been commonly achieved. l. ls Various factors influencing outcomes have been reported in the literature. I-IS Positive surgical margins lymph node invasion and distant metastasis have proved to be prognosticators for failure in all studies. The stages of primary colorectal cancer (TNM stage Dukes classification or status of mesenteric lymph nodes at the time of colorectal resection); the size number and lobar distribution of hepatic metastases; and the time from colorectal resection to hepatic metastasis (synchronous versus metachronous) have been identified as significant prognostic determinants. In some studies. blood transfusion during hepatectomy type of hepatic resection. histologic grades of primary and metastaric tumors serum CEA levels and gender have been found to be significant. Repeared hepatic Table 4. Tumor-Free Survival Prediction * Prediction Actuarial (Kaplan-Meier) So(t) (estimated) ly y y y Sy 6y 7y 8y 9y loy Tumor free survival prediccion based on patients with no risk iactors S(t)) corrd3ted well wirh 3ccuariai tumor-f". survival (Kaplan-Meier!. Data are presented as percentages

7 Vol. 189 No.3 September 1999 Iwatsuki et al Hepatic Resection Prognostic Scoring System _ iii.2: 7 ::I en 6 QI QI "- u.. 5.:. E 4 ::I I- QI 3 ;I I'll :; 2 E ::I 1. "=-: : ; 1 ; 1' : I : I :. I :... " I -. I : Grade 1 (n=32) Grade 2 (n=112) Grade 3 (n=47) Grade 4 (n=47) Grade 5 (n=5) Grade 6 (n=62) lime After Uver Resection (years) ;i' - iii. (I) II) e U-.!. E... II) = CO 'S E Grade 1 (n=2) Grade 2 (n=112) Grade 3 (n=47) Grade 4 (n=47) Grade 5 (n=5) *' oj( Time After Uver Resection (years) Figure 2. Kaplan-Meier tumor-free survival stratified by six grades. resection for recurrent metastases has been reported to prolong overall survival In our univariate analyses 1 of the 16 variables studied were significantly associated with overall patient and tumor-free survival (Table 1). Although our findings agree in general with othersi-18 some of the Figure 3. Estimated (Cox regression model) tumor-free survival stratified by five grades (grade 6 cannot be estimated with this model). individual variables that were significant in our investigation were not in several other studies. Except for genders none of the prognosticators noted in the univariate analysis have been reported in other studies to have an opposite association from the ones that we saw. Differences between our study and others are -. (f) II) co '3 E (J Grade 1 (n=32) Grade 2 (n=112) Grade 3 (n=47) Grade 4. (n=47) Grade 5 (n = 5) Grade 6 (n=62) co 6 t= :::s 5 U) -Q) 4..!! 3 e 2 :::s 1. '. -- Grade 1 (n=32) " Grade 2 (n=112) ""'-._.. Grade 3 (n=47). ""'" "" - Grade 4 (n=47) ""'" - Grade 5 (n=5). "' ---..QI-""" " "'" 'CJ'oo v lime After Uver Resection (years) Time After Liver Resection (years) Figure 't. Kapl;m-Mcicr overall patient survival stratitled bv six grades. Figure 5. Estimated (Cox regression model) overall patient survival stratified by five grades (grade 6 cannot be estimated with this model).

8 lwatsuki et a1 Hepatic Resection Prognostic Scoring System JAm Coil Surg mostly due to differences in the number of patients length of followup and grouping of continuous variables. The proposed formula derived from our current study (S(t) = So(t)]exp(R- Rl) appears to be simple and practical. It reflected reasonably well both tumor-free survival (Figs. 2 3) and over<tll patient survival (Figs. 4 5). Two other prognostic scoring systems for patients with hepatic metastases from colorectal carcinoma have been reported in the literature. The one proposed by Cady and Stone in 1991 included surgical margins the time to hepatic recurrence the number of metastases and serum CEA levels. Because this scoring system was not based on statistical analyses it could not be compared with ours. The second scoring system advanced in 1996 by Nordinger and associates 13 on behalf of a French surgical consortium was based on the study of patients collected from 85 institutions over the last 3 decades. The following seven factors were found to be significant by multivariate analysis: (1) age (6 or older versus less than 6 years) (2) serosal involvement of primary tumor (3) peritumorallymph node invasion by the primary (4) time to hepatic recurrence (more than 2 years versus 2 years or less) (5) tumor size (greater than 5cm versus 5cm or less) (6) number of tumors (four or more versus fewer than four) and (7) surgical margins (1 em or more versus less than 1 em). The patients were classified into three categories each with significantly poorer survival: grade 1 zero to two risk factors; grade 2 three to four risk factors; and grade 3 five to seven risk factors. This system was applied to our 144 patients with the best prognosis (ie those with our Pittsburgh grades 1 and 2). Our results with patients in grades 1 and 2 were essentially identical to those of the French13 grade 1 patients. Only 55 (38.2%) of these patients qualified for a French grade 1 however. The French grading system 13 failed to identify more than 6% of the patients with the most hopeful prognosis according (Q our Pittsburgh system. The failure of the French grading system (Q accurately predict the prognosis of our patients and especially those with Pittsburgh grades 1 and 2 may be related to several factors identifiable in the report by Nordinger and associates lj : (1) The two closely linked factors of serosal involvement and peritumoral lymph node invasion were designated as independent predictors in the French study by stepwise multivariate analysis; (2) a positive surgical margin was assumed if the tumor-free margin was less than 1 em inevitably excluding from the French grade 1 patients with negative and positive margins; (3) accrual of patients in the French study took place over 3 decades but was not analyzed by era; (4) the institutional factor (85 centers) was not examined 24 ; (5) more than 2 patients (including those with operative death) were excluded from the study; (6) age was not found to be a significant factor (p.5); and (7) death without recurrence was not censored in the calculation of tumor-free survival but was considered as death with recurrence. When the French group reanalyzed the factors influencing 5-year survival using the same database as in their previous report15 they found only three factors that influenced the 5-year survival: serosa infiltration peri tumoral lymph nodes and surgical margin of less than 1 cm. The factors of age time to hepatic recurrence tumor size and the number of metastases did not significantly influence survival at 5 years. In view of these disparities between our scoring system and the French system13 our Pittsburgh survival-prediction formula will have to be validated by other large series of patients. It is possible that refinements will be needed before it can be accepted universally. An international collaborative study by major centers could quickly accomplish this objective. Until then our results indicate the following. First excellent survival or even cure can be expected in more than one third of the patients with hepatic metastases if none or only one of the four risk factors is present (tumor number of three or more bilobar tumors tumor size greater than 8 em and time to hepatic recurrence of 3 months or less). Second the prognosis is extremely poor when all of the four risk factors are present when extrahepatic metastasis includes the lymph nodes or when the surgical margins are positive after hepatic resection. References 1. Fortner ]G. Silva ]S. Golby RB. et al. Multivariate analysis of a personal series of 247 consecutive patients with liver metastases from colorectal cancer. Ann Surg 1984; 199: Ekberg M. Tranberg KG. Anderson R. et al. Determinants of survival in liver resection for colorectal secondaries. Br J Surg 1986;73: Adson MA. Resection of liver metastases--when is it worthwhile? World J Surg 1987; 11 : Nordinger B. Parc R. Bdva E. et al. Hepatic resection for coloreccal liver metastases. Influence on survival of preoperative factors and surgery tor recurrences in 8 patients. Ann Surg 1987:25:

9 Vol. 189 No.3 September 1999 Iwatsuki et al Hepatic Resection Prognostic Scoring System Stephenson KR Steinberg SM Hughes KS et al. Perioperative blood transfusions are associated with decreased time to recurrence and decreased survival after resections of colorectal liver metastases. Ann Surg 1988;28: Hughes KS Simon RM Songhoraboodi S et al. Resection of the liver for colorectal carcinoma metastases: a multiinstitutional study of indications for resections. Surgery 1988; 13: Cady B Stone MD. The role of surgical resection of liver metastases in colorectal carcinoma. Semin Oncol 1991 :28: Doci R Gennari L Bignami P et al. One hundred patienrs with hepatic metastases from colorectal cancer treated by resection: analysis of prognostic determinanrs. Br J Surg 1991 :78: Scheele J Stangl R Altendorf-Hofman A Gall FP. Indicators of prognosis after hepatic resection for colorectal secondaries. Surgery 1991:11: Rose CB Nagarney DM Taswell HF et al. Perioperative transfusion and determinants of survival after hepatic resection for metastatic colorectal carcinoma. Ann Surg 1992:216:493-55: 11. Gayowski TJ Iwarsuki S Madariaga JR et al. Experience in hepatic resection for metastatic colorectal cancer: analysis of clinical and pathologic risk factors. Surgery 1994;116: Scheele J Stangl R Altendorf-Hofmann A Paul M. Resection of colorectalliver metastases. World J Surg 1995; 19: Nordinger B Guiguet M Vaillant J-C et al. Surgical resection of colorectal carcinoma metastases to the liver: a prognostic scoring system to improve case selection based on 1568 patients. Cancer 1996;77: Rees M Plant G Bygrave S. Late results justify resection for multiple hepatic metastases from colorectal cancer. Br J Surg 1997;84: Jaeck D Bachellier P Guiguet M et al. Long-term survival following resection of colorectal hepatic metastases. Br J Surg 1997; 84: Bakalakos EA Kim JA Young DC Martin EW Jr. Determinanrs of survival following hepatic resection for metastatic colorectal cancer. World J Surg 1998;22: Cady B Jenkins R Steele GD Jr et al. Surgical margin in hepatic resection for colorecta! metastasis: a critical and improveable determinant of outcome. Ann Surg 1998:227: Ohlsson BB Stenram U Tranberg KG. Resection of colorectal liver metastases: 25-year experience. World J Surg 1998:22: American Joint Committee on Cancer. AJCC Cancer Staging Manual. 5th ed. Philadelphia: Lippincott-Raven; 1997: International Union Against Cancer. TNM Classification ofmalignant Tumors. 5th ed. New York: Wiley-Liss; 1997: Fisher LD van Belle G. Biostatistics. A Methodology for the Health Sciences. New York: John Wiley & Sons Inc.: 1993: Nordinger B Vaillant J-C Guiguet M et al. Survival benefit of repeat liver resection for recurrent colorectal metastases: 143 cases. J Clin Oncol 1944; 12: Adam R Bismuth H Gastaing D et al. Repeat hepatectomy for colorectalliver metastasis. Ann Sueg 1997;225: DerSimonian R Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: